罗格列酮-二甲双胍治疗2型糖尿病疗效评价

胰岛素抵抗及胰岛β细胞功能进行性衰竭是2型糖尿病重要的发病机制.目前应用最广泛的改善胰岛素敏感性的两种药物即马来酸罗格列酮和盐酸二甲双胍,其复合片剂现已成功上市.本品具有良好的血糖控制、减轻胰岛素抵抗和保护胰岛13细胞功能等作用,可改善脂肪代谢和降低心血管事件危险因子及相关标志物水平等.本文简要综述罗格列酮.二甲双胍复方制剂的疗效及安全性.     

罗格列酮的药理学研究概况

在2型糖尿病进程中存在多种心血管危险因素。以胰岛素抵抗为核心,可导致高血糖、高血压、微量白蛋白尿(MA)、炎症、高纤溶状态、脂代谢异常、内皮功能障碍、动脉粥样硬化和心血管病。罗格列酮(rosiglitazone)是一种新型的噻唑烷二酮类(TZD)胰岛素增敏剂,为过氧化物酶增殖物激活的受体(PPAR r)的激动剂,调控与胰岛素效应有关的多种基因转录,减轻对胰岛B细胞的脂毒性,从而改善胰岛B细胞的功能[1]。1999年罗格列酮在美国上市,未发现其同类药物曲格列酮(troglitazone)可能引起的肝毒性。作为胰岛素增敏剂,直击胰岛素抵抗,在控制血糖的同时,…     

胰岛素联合罗格列酮治疗2型糖尿病患者疗效观察

目的比较胰岛素联合罗格列酮和单用胰岛素治疗2型糖尿病（T2DM）患者的疗效。方法将120例T2DM患者分成治疗组（胰岛素加罗格列酮）与对照组（胰岛素治疗），随访观察12周。结果2组患者治疗后血糖均得到良好控制，但治疗组胰岛素日需求量明显低于对照组（P〈0．01）；与对照组相比，治疗组血甘油三酯下降，而高密度脂蛋白胆固醇升高（P〈0．05），B细胞功能指数升高（P〈0．05），胰岛素抵抗指数显著降低（P〈0．05），脂联素水平升高（P〈0．01）。结论罗格列酮与胰岛素联用能使2型糖尿病患者血糖、血脂改善，增加胰岛素敏感性，降低胰岛素抵抗，升高脂联素水平，优于单用胰岛素治疗。     

吡格列酮对初诊2型糖尿病强化治疗的影响

由于胰岛素抵抗及其相关的代偿性高胰岛素血症是引起胰岛β细胞功能不全进展的病因之一,故纠正或减轻胰岛素抵抗可减慢或防止胰岛素抵抗相关性糖尿病病人胰岛β细胞功能的进一步恶化。由于噻唑烷二酮类药物是减轻胰岛素抵抗的最有效的药物,可以预期这类药物治疗将减慢或防止胰岛β细胞功能的进一步恶化。因此,通过观察胰岛素强化治疗及其与口服噻唑烷二酮类药物联合治疗,了解其对初诊2型糖尿病患者近期血糖控制的影响。     

罗格列酮在胰岛素抵抗糖尿病患者中的应用

目的探讨罗格列酮在胰岛素抵抗糖尿病患者中的临床疗效。方法选择对胰岛素强化治疗无效的胰岛素抵抗患者39例,采用罗格列酮增敏配合胰岛素强化治疗,观察治疗前后空腹血糖（FBG）、餐后2h血糖（2hPG）水平并比较。结果采用增敏法治疗后FBG与2hPG水平均明显改善,差异有统计学意义（P〈0.01）。结论采用罗格列酮增敏胰岛素强化治疗胰岛素抵抗的糖尿病患者,血糖控制效果满意。     

联合罗格列酮治疗2型糖尿病疗效观察

随着人们生活方式的改变及人口老龄化 ,2型糖尿病的发病率呈逐年上升趋势。近年来 ,实验研究及临床观察均证实 2型糖尿病是以胰腺 β细胞分泌胰岛素功能受损、肝脏和外周组织出现胰岛素抵抗并存为特征的 ,其中胰岛素抵抗是根本的病理生理。因此 ,降低胰岛素抵抗是治疗 2型糖尿病的重要环节。罗格列酮 (rosiglitazone,由史克必成天津有限公司提供 )为胰岛素增敏剂 ,属新一代噻唑烷二酮类药物。该药能缓解胰岛素抵抗、长期稳定控制血糖 ,起到减少并发症和延缓病情进展的作用。自 2 0 0 2年 2月至 11月 ,我科采用联合罗格列酮治疗 2型糖尿病血…     

罗格列酮内治疗2型糖尿病86例疗效观察

目的观察罗格列酮内治疗2型糖尿病的疗效。方法86例2型糖尿病患者：在应用其它适量降糖药物的同时加用罗格列酮内4 mg/d,共用6个月。观察前后空腹血糖（FPG）,餐后血糖（PPG）,糖化血红蛋白（HbA1c）,甘油三酯（TG）,低密度脂蛋白（LDL）,空腹胰岛素（FINS）,体重指数（BMI）。结果治疗前后上述指标均明显下降（P〈0.05）。结论罗格列酮内能安全、有效改善血糖水平,降血脂、减轻胰岛素抵抗,提高胰岛素敏感性,改善胰岛B细胞功能。     

罗格列酮治疗2型糖尿病合并轻度高血压36例

有研究表明,2型糖尿病与高血压患者均存在胰岛素抵抗,而胰岛素增敏药噻唑烷二酮类药物有改善胰岛素抵抗的作用。我们使用罗格列酮治疗了36例2型糖尿病合并轻度高血压的患者,旨在观察罗格列酮对2型糖尿病合并高血压患者的效果。     

马来酸罗格列酮的药理学与临床疗效

糖尿病是碳水化合物、脂肪和蛋白质代谢紊乱综合征 ,主要特征为慢性高血糖血症 ,Ⅱ型糖尿病是该种疾病最常见的形式。其基本病理生理特征是β细胞分泌胰岛素障碍和外周组织对胰岛素抵抗导致的代谢异常。马来酸罗格列酮是一种高效口服抗糖尿病药物 ,主要成分属噻唑烷二酮类。该类药物被称为“胰岛素增敏药” ,可降低靶组织对胰岛素的抵抗和增加肝脏、脂肪及肌肉对血液中胰岛素的敏感性。研究表明罗格列酮可降低胰岛素分泌 ,同时有效控制血糖 ,因此应用此药治疗可降低胰岛细胞的功能衰竭及低血糖的危险[1 ,2 ] 。1　药效学1 .1　作用机制　临床前期药理研究表明 ,马来酸罗格列酮是高选择性的且作用很强的过氧化物酶体增殖活化受体γ(ＰＰＡＲγ)激动药。马来酸罗格列酮的胰岛素增敏作用是通过与ＰＰＡＲγ结合并使之活化 ,进而增加多种蛋白质的合成。这些蛋白质在细胞对胰岛素产生生物反应时参与葡萄糖转运和利用以及脂肪代谢过程[2 ] 。马来酸罗格列酮改善胰岛素敏感性的另一机制是通过增强葡萄糖转运子ＧＬＵＴ 4对葡萄糖的摄取。经马来酸罗格列酮活化的ＰＰＡＲγ可增强ＧＬＵＴ 4的表达 ,使其向细胞表面移位并对胰岛素作出反应 ,导致葡萄糖摄取增加 ,从...     

三联疗法治疗磺酰脲类药物继发失效2型糖尿病的临床观察

目的:观察甘精胰岛素、瑞格列奈、罗格列酮联合治疗磺酰脲类药物继发失效(SFS)的2型糖尿病(T2DM)患者的血糖(BG)控制和胰岛B细胞功能恢复情况。方法:选择26例三联疗法治疗的SFS患者,采用自身前、后对照观察空腹血糖(FPG)、餐后2 h血糖(2hPG)、空腹基础C肽值(FC-P)、餐后2hC肽值(2hC-P)、糖化血红蛋白(HbA1c)等变化。结果:与治疗前比较,甘精胰岛素、瑞格列奈、罗格列酮联合治疗SFS的T2DM,BG控制理想,胰岛B细胞功能改善均有统计学意义(P<0.05)。结论:甘精胰岛素、瑞格列奈、罗格列酮三联疗法能有效控制SFS的T2DM患者BG,并能改善胰岛B细胞功能。     

The use of animal models in diabetes research

Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients.     

Modulatory effect of insulin on T cell receptor mediated calcium signaling is blunted in long lasting type 1 diabetes mellitus

Insulin significantly influences Ca(2+) signals evoked by various stimulants. In type 1 recent onset diabetes mellitus the proliferative response of T cells is significantly decreased. The number of clinical trials exploring the role of anti-CD3 monoclonal antibodies (mAb) as a therapeutic agent in recent onset diabetes mellitus type 1 is increasing last years. Therefore, a better understanding of the interplay between T cell receptor (TCR) dependent Ca(2+) increase, and insulin is of vital clinical significance. The aim of the study was to assess the effect of insulin on TCR evoked Ca(2+) responses in T lymphocytes obtained from healthy volunteers and patients suffering from long lasting diabetes mellitus type 1. Analysis was performed with use of the flow cytometer. We demonstrated that T cells ability to mobilize Ca(2+) was significantly reduced in long lasting diabetes mellitus type 1. Ca(2+) decrease achieved by the long term incubation with anti-CD3 mAb in T cells from healthy volunteers was restored by insulin. Strong interrelationship between baseline Ca(2+) level and plateau phase response to TCR stimulation was observed in the cytoplasm of cells pre-incubated with insulin from both healthy subjects and diabetic patients (r = 0.95, p < 0.0001 and r = 0.94, p < 0.0001, respectively). We postulate the existence of the interplay between TCR mediated activation and insulin. The TCR-insulin interplay is blunted in long lasting diabetes mellitus type 1. These observations may have an important implication for future therapeutic options in diabetes.     

二肽基肽酶Ⅳ抑制剂辅助胰岛素治疗1型糖尿病的研究进展

二肽基肽酶Ⅳ（DPP-4）抑制剂为一类在2型糖尿病中应用广泛的口服降糖药,其疗效确切、给药方便、总体耐受性好,但目前尚未被批准用于1型糖尿病。国内外相关文献表明在1型糖尿病患者体内DPP-4抑制剂可以辅助胰岛素改善血糖、保护胰岛β细胞功能、降低谷氨酸脱羧酶抗体（GADA）滴度、减少胰岛素剂量,且不增加低血糖风险和体质量。因此,DPP-4抑制剂可能可作为1型糖尿病患者胰岛素的辅助治疗,作用机制可能源于其抑制胰岛α细胞分泌胰高血糖素,通过免疫机制使胰岛β细胞免受摧毁。     

How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes

Metabolic diseases are associated with activation of the innate immune system in various tissues and characterized by elevated inflammatory factors and the presence of immune cells. Type 2 diabetes develops when islet beta cells are deficient in producing sufficient insulin to overcome peripheral insulin resistance. Intra-islet IL-1β activity diminishes beta cell function and survival and governs islet inflammation. Targeting the IL-1 system with the IL-1 receptor antagonist IL1Ra improved insulin secretion, glycaemia and reduced systemic inflammation in a proof of concept study with patients with type 2 diabetes. Currently, long lasting and specific IL-1β blocking antibodies are being evaluated in clinical trials and this may lead to a novel cytokine-based treatment for type 2 diabetes.     

Generation, validation and humanisation of a novel insulin resistant cell model

Insulin resistance is a characteristic of type 2 diabetes and is a major independent risk factor for progression to the disease. In particular, insulin resistance associates with increased body fat and almost certainly contributes to the dramatic increase in risk of type 2 diabetes associated with obesity. Therefore, in order to design truly effective insulin sensitising agents, targeted at the mechanism of disease development, we aimed to generate an obesity-related insulin resistant cell model. Rat hepatoma cells were grown in the presence of serum isolated from obese rodents or obese human volunteers, and the insulin sensitivity of the cells monitored over time by measuring a well-characterised insulin regulated gene promoter. Higher insulin concentrations were required to fully repress the gene in the cells grown in obese rodent serum compared with those grown in serum from lean rodents (almost a 10-fold shift in insulin sensitivity). This was reversed by restoration of normal growth medium, while the insulin resistance was prevented by pioglitazone or metformin. Meanwhile, growth of cells in serum collected from obese human volunteers with diabetes also reduced the insulin sensitivity of the rat cells. No clinical marker predicted the degree of insulin resistance that was generated by the human serum. We have developed a novel insulin resistant cell model for the study of the molecular development of obesity-linked insulin resistance, screen for compounds to overcome obesity-related insulin resistance and potentially search for novel serum biomarkers of insulin resistance.     

Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders

The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.     

Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus

Insulin aspart (NovoRapid, NovoLog) is a short-acting insulin analogue, which has a faster onset and shorter duration of action than regular human insulin. Insulin aspart administered immediately before meals provided significantly greater improvements in glycosylated haemoglobin and better postprandial glycaemic control than regular human insulin administered 30 minutes before meals, when used in a basal-bolus regimen with neutral protamine Hagedorn (NPH) insulin, in randomised, nonblind studies in patients with type 1 diabetes mellitus. In patients with type 2 diabetes, insulin aspart provided similar glycaemic control to regular human insulin, administered in a basal-bolus regimen with NPH insulin. Small studies suggest that the use of insulin aspart in combination with oral hypoglycaemic agents may be beneficial. Insulin aspart, administered by continuous subcutaneous insulin infusion (CSII) provided better glycaemic control than insulin aspart multiple daily injection regimens in patients with type 1 (but not type 2) diabetes, and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Limited studies show insulin aspart to be effective in children, adolescents and young adults with type 1 diabetes. Insulin aspart had a tolerability profile similar to that of regular human insulin in clinical trials. The incidence of major or nocturnal hypoglycaemic events reported in patients receiving insulin aspart was lower than that of regular human insulin in several studies.In conclusion, insulin aspart, administered immediately before meals in a basal-bolus regimen with NPH insulin, provided better long-term glycaemic control than regular human insulin administered 30 minutes before meals in patients with type 1 diabetes, and was as effective as regular human insulin in patients with type 2 diabetes. A significantly lower risk of hypoglycaemia was seen in several trials. Insulin aspart CSII provided better glycaemic control than insulin aspart multiple daily subcutaneous injection (MDI) in patients with type 1 (but not type 2) diabetes and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Insulin aspart is an effective and well tolerated alternative to regular human insulin and insulin lispro for the maintenance of glycaemic control in patients with type 1 or 2 diabetes.     

2型糖尿病合并视网膜病变病人的胰岛功能分析

目的　研究 2型糖尿病视网膜病变病人的胰岛分泌情况。方法　应用葡萄糖 胰岛素释放实验对2型糖尿病病人 98例 (其中 6 6例视网膜病变病人 ,无视网膜病变组病人 32例 )、正常对照组 32例进行血糖、胰岛素测定 ,计算血糖及胰岛素曲线面积、胰岛素敏感性指数、胰岛素分泌指数并进行比较。结果　糖尿病两组各时相血糖值及血糖面积均非常显著高于正常对照组 ;糖尿病有视网膜病变组各时相血糖值及血糖面积均显著高于无视网膜病变组 (P <0 0 1) ;糖尿病有视网膜病变组各时相胰岛素值及胰岛素面积均显著低于无视网膜病变组 (P <0 0 1) ;糖尿病有视网膜病变组的胰岛素分泌指数显著低于无视网膜病变组 (P <0 0 1)。多元逐步回归分析表明 ,视网膜病变与病程呈正相关 ,与胰岛素分泌指数负相关 (P <0 0 1)。结论　 2型糖尿病视网膜病变的病人存在着严重的持续高血糖 ,胰岛素分泌障碍是 2型糖尿病视网膜病变的危险因素。     

广东籍Ⅱ型糖尿病患者胰岛素受体基因变异的研究

目的 探讨胰岛素受体基因(IRG)变异与Ⅱ型糖尿病(Ⅱ型DM)患者胰岛素抵抗(IR)的关系.方法 运用聚合酯链反应及单链构型多态性(PCR-SSCP)对57例广东籍Ⅱ型DM和对照组健康人40人的IRG17外显子进行筛查,并对其进行DNA测序.结果 57例广东籍Ⅱ型DM和对照组健康人40人的IRG17外显子均为野生型(CGGCATGGTGT),未发现基因多态性和点突变.结论 胰岛素受体基因变异可能不是广东籍Ⅱ型DM患者发病和IR的原因.     

半月疗法恢复初发2型糖尿病患者血糖稳态的临床研究

目的总结分析采用胰岛素半月疗法强化治疗和口服降糖药物治疗初发2型糖尿病的长期疗效。方法对60例初发2型糖尿病患者随机分为两组，观察组30例采用胰岛素泵持续胰岛素输注和对照组30例口服降糖药物治疗，比较两种方法治疗前后空腹血糖、空腹血浆胰岛素水平以及餐后血糖、餐后血浆胰岛素水平等指标，并对结果进行分析。结果观察组血糖控制达标时间为（1．2±0．3）周，对照组为（7．8±0．6）周，观察组在使用胰岛素泵强化治疗两周后停药，连续观察58周，血糖长期稳定达标，其胰岛素抵抗指数无明显增加（P〉0．05）；对照组使用降糖药物治疗达标12周后停药，无法达到血糖控制目标（无法停药）。结论对初发2型糖尿病患者，尤其以餐后血糖升高为主者，通过胰岛素半月疗法强化治疗，可以使其胰岛细胞的功能恢复到2型糖尿病自然病程的早期，仅通过饮食和运动控制，即可获得长期良好的血糖控制。此治疗方法可以作为初发2型糖尿病治疗的可行性方案。